Tissue Distribution, Gender-Divergent Expression, Ontogeny, and Chemical Induction of Multidrug Resistance Transporter Genes (Mdr1a,Mdr1b,Mdr2) in Mice

Abstract

ABSTRACT:Multidrug resistance (Mdr) transporters are ATP-binding cassette transporters that efflux amphipathic cations from cells and protect tissues from xenobiotics. Unfortunately, Mdr transporters also efflux anticancer drugs from some tumor cells, resulting in multidrug resistance. There are two groups of Mdrs in mice: group I includes Mdr1a and Mdr1b that transport xenobiotics, whereas group II is Mdr2, a flipase that facilitates phospholipid excretion into bile. Little is known about the regulation of Mdr genes in vivo. The purpose of this study was to determine tissue distribution, gender differences, ontogeny, and chemical induction of Mdrs in mice. The mRNA of Mdr1a is highest in gastrointestinal tract, Mdr1b in ovary and placenta, and Mdr2 in liver. Both Mdr1a and Mdr1b in kidney show female-predominant expression patterns due to repression by androgens. The ontogeny of mouse Mdr1a in duodenum and brain as well as Mdr1b in brain, kidney, and liver all share a similar developmental pattern: low expression at birth, followed by a gradual increase to mature levels at approximately 30 days of age. In contrast, Mdr2 mRNA in liver is markedly up-regulated at birth, which returns to low levels by 5 days of age and then gradually increases to mature levels. None of the Mdrs in liver are readily inducible by any class of microsomal enzyme inducers. In conclusion, the three Mdr transporters in mice are expressed in a tissue-specific and age-dependent pattern, there are gender differences in expression, and Mdr transporters are inducible by only a few microsomal enzyme inducers.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…Mdr1a mRNA is most prominent in the large intestine followed by the small intestine, kidneys, and brain ( Fig. 4) (Cui et al, 2009c). Meanwhile, Mdr1b expression is highest in the kidneys, lungs, brain, ovaries, and placenta ( Fig.…”

Acetaminophen Modulates P-Glycoprotein Functional Expression at the Blood-Brain Barrier by a Constitutive Androstane Receptor–Dependent Mechanism

“…Female rats were selected to maintain consistency with previous work (Seelbach et al, 2007;. Additionally, female rodents are preferable to males for transport studies since androgens have been shown to repress functional expression of ATP-binding cassette transporters (Cui et al, 2009). APAP (250 and 500 mg/kg) was prepared in 100% DMSO.…”

The Role of Canalicular ABC Transporters in Cholestasis

“…3) (Zhang, 1996). ABCB4 is predominantly expressed in the apical membrane of hepatocytes (Yoshikado et al, 2011;Pasmant et al, 2012), although low levels of mRNA transcripts have been detected in the adrenal glands, heart, striated muscles, tonsils, placenta, and brain Patel et al, 2003;Augustine et al, 2005;Kim et al, 2008;Cui et al, 2009). This expression pattern supports its role as the major canalicular PC transporter in humans.…”